The invention relates to xcex1-amino acid phenyl ester derivatives, to pharmaceutical compositions containing the same, as well as to the use of these xcex1-amino acid phenyl ester derivatives as hypnotics for the induction and maintenance of general anaesthesia.
It has been reported (G. Brancaccio and A. Larizza, II Farmaco 1964, 19, 986-1002) that xcex1-amino acid phenyl ester derivatives, wherein the amino group is either dialkylated or is part of an heterocyclic system (GB 1,102,011: Richardson-Merrell S.p.A.), possess local anaesthetic activity, with piperazinyl derivatives proving the most active. In GB 1,160,468 (May and Baker Ltd.) an xcex1-amino acid phenyl ester wherein the amino group is part of a morpholinyl ring, i.e. 2,6-dimethoxyphenyl 2-morpholinopropionate, is disclosed as an intravenous general anaesthetic having a short duration of activity with rapid, smooth recovery. The hypnotic properties of this compound are attained at rather high dose levels and consequently there exists a need for new water soluble intravenous general anaesthetics with improved potency.
The present invention provides xcex1-amino acid phenyl ester derivatives having the general formula I 
wherein
R1 is (C1-3)alkyloxy;
R2 is (C1-3)alkyl, (C1-3)alkyloxy or (C2-3)alkenyl;
R3 is hydrogen, (C1-3)alkyl, (C1-3)alkyloxy or (C2-3)alkenyl;
R4 is (C1-6)alkyl;
R5 and R6 are independently (C1-6)alkyl, (C2-6)alkenyl, (C2-6)alkynyl or aralkyl, each of which may be optionally substituted with (C1-3)alkyloxy, (C1-3)alkyloxycarbonyl, cyano or NR7R8;
R7 and R8 are independently (C1-6)alkyl;
or a pharmaceutically acceptable salt thereof, with the exclusion of 2,6-dimethoxyphenyl 2-(diethylamino)propionate and 2,6-dimethoxyphenyl 2-(diethylamino)butyrate.
Since 2,6-dimethoxyphenyl 2-(diethylamino)propionate and 2,6-dimethoxyphenyl 2-(diethylamino)butyrate have been described as local anaesthetics by G. Brancaccio and A Larizza (vide supra), no protection is sought for these compounds per se.
The xcex1-amino acid phenyl ester derivatives of formula I, having a dialkylated amino group, were surprisingly found to be potent intravenous hypnotics with quick onset, and a short duration of action with rapid, smooth recovery.
The term (C1-6)alkyl, as used in the definition of formula I, means a branched or unbranched alkyl group having 1-6 carbon atoms, like hexyl, pentyl, isobutyl, tertiary butyl, propyl, isopropyl, ethyl and methyl. The term (C1-3)alkyl means an alkyl group having 1-3 carbon atoms, like n-propyl, isopropyl, ethyl and methyl. In the term (C1-3)alkyloxy as used in formula I, (C1-3)alkyl has the meaning as previously given, preferably methyl. The term (C2-6)alkenyl means a branched or unbranched alkenyl group having 2-6 carbon atoms, like for example hexenyl, pentenyl, butenyl, 1,3-butadienyl, 1-methyl-propen-2-yl, propen-2-yl(allyl), propen-1-yl or ethenyl(vinyl). Alkenyl groups having at least 3 carbon atoms may be in the E- or Z-form, or a mixture thereof. The term (C2-3)alkenyl means an alkenyl group having 2 or 3 carbon atoms, like propen-2-yl, propen-1-yl or ethenyl(vinyl).
The term (C2-6)alkynyl means a branched or unbranched alkynyl group having 2-6 carbon atoms, like hexynyl, pentynyl, butynyl, propyn-2-yl or ethynyl. The term aralkyl means an aryl(C1-3)alkyl group, wherein alkyl means a bivalent carbon radical having 1-3 carbon atoms, such as methylene, ethan-1,2diyl, propan-1,3-diyl, ethylidene or propylidene, and wherein aryl means a C6-12 aromatic group and includes one or two C6-aromatic rings, like for example phenyl, naphthyl or biphenyl.
Preferred xcex1-amino acid phenyl ester derivatives of the invention correspond to compounds having formula I wherein R1 and R2 are methoxy; and R4 is (C2-3)alkyl, like ethyl, propyl or isopropyl, and wherein R3, R5 and R6 have the previously given meanings. Further preferred are compounds of formula I wherein R1 and R2 are methoxy, R3 is hydrogen or (C1-3)alkyl, R4 is (C2-3)alkyl and wherein R5 and R6 are independently (C1-6)alkyl or aralkyl, each of which may be optionally substituted with (C1-3)alkyloxy. More preferred are the compounds wherein R1 and R2 are methoxy, R3 is hydrogen or methyl, R4 is (C2-3)alkyl, and R5 and R6 are independently methoxyethyl or ethoxyethyl. Especially preferred xcex1-amino acid phenyl ester derivatives of the invention correspond to formula I wherein R1 and R2 are methoxy; R3 is hydrogen or methyl; R4 is ethyl; and R5 and R6 are methoxyethyl.
The compounds of formula I and their salts contain at least one centre of chirality, i.e. at the xcex1-carbon atom, and exist therefore as stereoisomers, including enantiomers and, when appropriate, diastereomers. The present invention includes the aforementioned stereoisomers within its scope and each of the individual R and S enantiomers of the compounds of formula I and their salts, substantially free, i.e. associated with less than 5%, preferably less than 2%, in particular less than 1% of the other enantiomer, and mixtures of such enantiomers in any proportions including the racemic mixtures containing substantially equal amounts or the two enantiomers.
Preferred are the xcex1-amino acid phenyl ester derivatives of formula I wherein the configuration at the xcex1-carbon atom is that of the R-enantiomer. Particular preferred compounds according to the invention, which have found to be useful as hypnotics for intravenous anaesthesia, are:
R-2-[N-bis(2-methoxyethyl)amino]butyric acid 2,6-dimethoxy-4-methylphenyl ester;
R-2-[N-bis(2-methoxyethyl)amino]butyric acid, 2,6-dimethoxyphenyl ester; and pharmaceutically acceptable salts thereof.
xcex3-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter within the central nervous system and it is probable that compounds potentiating the effects of GABA at GABAA receptors will induce anaesthesia (S. A. Zimmerman, M. V. Jones and N. L. Harrison, J. Pharmacol. Exp. Therap. 1994, 270, 987-991; N. P. Franks and W. R. Lieb, Nature 1994, 367, 607-614). Indeed there is compelling evidence that many hypnotics exert their biological activity via modulation of GABAA receptors, including steroids, barbiturates, benzodiazepines and propofol (D. L. Tanelian, P. Kosek, I. Mody and M. B. Maclver, Anesthesiology 1993, 78, 757-776). The compounds of the present invention have been shown to allosterically modulate GABAA receptors by inhibiting the specific binding of the radioligand [35S]-tert-butyl bicyclophosphorothionate to rat whole brain membranes. The in vitro results presented in Table 1 demonstrate modulation of GABAergic function by the compounds of the present invention and suggest this mechanism mediates or enhances their hypnotic activity.
In addition to their general anaesthetic activity, the compounds of the invention can be used as sedative and analgesic drugs and in the treatment of GABA related diseases, such as anxiety (e.g. panic attack), stress, sleep disorders, post natal depression, and premenstrual tension, and in the alleviation of seizure.
The invention also relates to pharmaceutical compositions comprising an xcex1-amino acid phenyl ester derivative having the general formula I or a pharmaceutically acceptable salt thereof.
The compounds of the invention may be prepared by condensation of an appropriately R1,R2,R3-substituted phenol, wherein R1, R2 and R3 have the previously given meanings, with an acid halogenide according to the formula Hal1-CHR4xe2x80x94CO-Hal2, wherein R4 has the meaning as previously defined and Hal1 and Hal2 are independently iodo, bromo or chloro, preferably bromo, after which the resulting intermediate ester derivative of formula II 
is reacted with an amine according to the formula R5R6NH, wherein R5 and R6 have the meanings as previously defined, optionally followed by conversion into a pharmaceutically acceptable salt.
The acid halogenide according to the formula Hal1-CHR4xe2x80x94CO-Hal2 may be prepared from the xcex1-halogeno acid Hal1-CHR4xe2x80x94COOH by treatment with an inorganic acid halide, such as thionyl chloride, or an organic acid halide, such as oxalyl chloride. The intermediate xcex1-halogeno acid Hal1-CHR4xe2x80x94COOH can be prepared using methods well known to the skilled person, for example by treatment of the corresponding xcex1-amino acid, NH2xe2x80x94CR4xe2x80x94COOH with sodium nitrite in aqueous hydrobromic acid.
Alternatively the intermediate ester derivative of formula II may be prepared by condensation of an appropriately R1,R2,R3-substituted phenol, wherein R1, R2 and R3 have the previously given meanings, with an acid according to the formula Hal1-CHR4xe2x80x94CO2H, wherein R4 has the meaning as previously defined and Hal1 is iodo, bromo or chloro, preferably bromo, with the aid of a condensing agent, such as bromo-trispyrrolidino-phosphonium hexafluorophosphate (PyBrop), dicyclohexyl-carbodiimide/N-hydroxybenzotriazole and the like.
The compounds of the invention may also be prepared by condensation of an appropriately R1,R2,R3-substituted phenol, wherein R1, R2 and R3 have the previously given meanings, with an xcex1-amino acid derivative according to the formula R5R6Nxe2x80x94CHR4xe2x80x94CO2H, wherein R4, R5 and R6 have the previously given meanings, with the use of a condensation agent, such as those mentioned above.
The xcex1-amino acid phenyl ester derivatives of Formula I contain at least one chiral carbon atom, i.e. the xcex1-carbon atom. The compounds can therefore be obtained as pure stereoisomers, or as a mixture of stereoisomers. Methods for asymmetric synthesis whereby the pure stereoisomers are obtained are well known in the art, e.g. synthesis with chiral induction, enantioselective enzymatic ester hydrolysis, separation of stereoisomers or enantiomers using chromatography on chiral media. Such methods are for example described in Chirality in Industry (edited by A. N. Collins, G. N. Sheldrake and J. Crosby, 1992; John Wiley).
Pharmaceutically acceptable salts may be obtained by treating the free base of the compounds according to formula I with a mineral acid such as hydrochloric acid, hydrobromic acid, phosphoric acid, and sulphuric acid, or with an organic acid such as for example ascorbic acid, citric acid, tartaric acid, lactic acid, maleic acid, malonic acid, fumaric acid, glycolic acid, succinic acid, propionic acid, acetic acid, methanesulphonic acid and the like.
The present invention further provides pharmaceutical compositions comprising an xcex1-amino acid phenyl ester derivative having the general formula I, or a pharmaceutically acceptable salt thereof, in admixture with pharmaceutically acceptable auxiliaries, and optionally other therapeutic agents. The term xe2x80x9cacceptablexe2x80x9d means being compatible with the other ingredients of the composition and not deleterious to the recipients thereof. Compositions include e.g. those suitable for oral, sublingual, subcutaneous, intravenous, intramuscular, local, or rectal administration, and the like, all in unit dosage forms for administration.
For oral administration, the active ingredient may be presented as discrete units, such as tablets, capsules, powders, granulates, solutions, suspensions, and the like. For parenteral administration, the pharmaceutical composition of the invention may be presented in unit-dose or multi-dose containers, e.g. injection liquids in predetermined amounts, for example in sealed vials and ampoules, and may also be stored in a freeze dried (lyophilized) condition requiring only the addition of sterile liquid carrier, e.g. water, prior to use. Mixed with such pharmaceutically acceptable auxiliaries, e.g. as described in the standard reference, Gennaro et al., Remington""s Pharmaceutical Sciences, (18th ed., Mack Publishing Company, 1990, see especially Part 8: Pharmaceutical Preparations and Their Manufacture), the active agent may be compressed into solid dosage units, such as pills, tablets, or be processed into capsules or suppositories. By means of pharmaceutically acceptable liquids the active agent can be applied as a fluid composition, e.g. as an injection preparation, in the form of a solution, suspension, emulsion, or as a spray, e.g. a nasal spray. For making solid dosage units, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive which does not interfere with the function of the active compounds can be used. Suitable carriers with which the active agent of the invention can be administered as solid compositions include lactose, starch, cellulose derivatives and the like, or mixtures thereof, used in suitable amounts. For parenteral administration, aqueous suspensions, isotonic saline solutions and sterile injectable solutions may be used, containing pharmaceutically acceptable dispersing agents and/or wetting agents, such as propylene glycol or butylene glycol. The invention further includes a pharmaceutical composition, as hereinbefore described, in combination with packaging material suitable for said composition, said packaging material including instructions for the use of the composition for the use as hereinbefore described. The compounds of the invention may be administered for humans in a dosage of 0.001-50 mg per kg body weight, preferably in a dosage of 0.1-20 mg per kg body weight.
The invention is illustrated by the following examples.